Bone Marrow Adipose Tissue
7. BM ADIPOCYTES AND HEMATOPOIESIS
These contrasting properties are all the more puzzling, as adipocytes and osteoblasts share a common progenitor, the MSC. These distinct characteristics (probably because of different secretory and/or surface factors) could be significant in some situations, such as increased BM adipogenesis during aging or osteoporosis.
What are the hematopoietic effects of the products more specifically secreted by adipocytes, namely cytokines, leptin and adiponectin?
• BM adipocytes in primary culture secrete only trace amounts of IL-1Gand TNF-F. On the contrary, they produce significant levels of IL-6, a secretion stimulated by both IL-1Gand TNF-F(200). Besides having a proinflammatory effect, IL-6 is an important regulator of marrow hematopoiesis. The number of IL-6 receptors on hematopoietic pro- genitor cells increases significantly with maturation of these cells (201), and IL-6 is a regulator of granulopoiesis in vivo (202). IL-6 is also involved in normal B-cell differen- tiation, and is a key growth and survival factor for malignant B-cells in multiple myeloma (203).
• We first reported that human BM adipocytes secrete large quantities of leptin (63), which appears to play a part in the regulation of hematopoietic progenitors and their differentiation into granulocyte and monocyte precursors. The concentration of leptin required for this effect in vitro (50–100 ng/mL) is rather high, but is within the range of plasma leptin levels observed in obese subjects (64). As leptin concentrations in bone marrow and plasma are highly correlated in humans (64), is leptin involved in the leukocytosis associated with obesity and, more broadly, is there any correlation between leptin levels and blood cell counts? Wilson et al. observed that in obese Pima Indians most of the variance in the leukocyte count attributable to body fat could be accounted for by plasma leptin concentration (204). We confirmed that leptin and leukocyte count are also correlated in French obese subjects (64). Concerning nonobese subjects, Togo et al. (205) reported a negative correlation between leptin and hemoglobin levels in adult Japanese males, but no correlation between leptin levels and leukocyte counts. On the contrary, an association of serum leptin level with leukocyte and erythrocyte counts in adolescent Japanese males aged 15 to 16 yr was reported by Hirose et al. (206). In a large population of European subjects, we observed that there was no statistically significant relationship between circulating leptin levels and blood cell parameters in healthy middle-aged men and women.
However, a role for high leptin concentrations in situations such as obesity or sepsis cannot be excluded, as suggested by the weak correlation we observed in hospitalized patients (207).
• In vitro, leptin modulates cytokine secretion from T-lymphocytes and macrophages, increases the proliferation of naive T-cells while reducing the proliferation of memory T-cells, and enhances the phagocytic activity of mature macrophages (58). Mice with leptin deficiency or resistance have reduced T-cell function. The decrease in leptin that accompanies starvation or food restriction also induces immune suppression, probably through downregulation of the T-cell response (208,209).
• In conclusion, leptin probably plays a direct role in the proliferation of BM hematopoietic progenitors and their differentiation along the granulocyte–macrophage and naive T-cell lineages. In situations with high levels of circulating leptin (inflammation, obesity) or with falling leptin levels (starvation), a regulatory role on immune response is likely, either directly or indirectly through its effects on other cells of the microenvironment and on cytokines.
Fig. 3. Regulating effects of leptin and adiponectin on hematopoietic differentiation. MSC: mesen- chymal stem cell; HSC: hematopoietic stem cell; G-M: granulocytes and monocytes/macrophages; E- Meg: erythroblasts and megakaryocytes.
As previously indicated, adiponectin serves as a negative regulator for myelo- monocytic progenitor growth and inhibits macrophage functions (77). In that respect, adiponectin is a negative regulator of the immune response at two levels: it suppresses the phagocytosis of mature macrophages and inhibits the growth of macrophage precur- sors. Addition of adiponectin to long-term bone marrow cultures influences the earliest lymphocyte precursors and strongly inhibits B-lymphopoiesis (76).
Overall, leptin exerts a proinflammatory role and adiponectin appears to act as an anti- inflammatory molecule (210). The effects of adiponectin and leptin on hematopoiesis, immunity, and inflammation appear to be diametrically opposite (Fig. 3).
8. CONCLUSIONS
Well over a decade after the paper published in 1990 by Gimble (1), we are still asking questions about the function of adipocytes in the bone marrow stroma. Plastic BM adipose tissue does not simply fill bone cavities that are not needed for hematopoietic activity. It may serve as an energy store for local needs (i.e., hematopoiesis and bone modeling) or participate in the overall energy metabolism of the body. Curiously, since the pioneering works of Tavassoli et al. (23,26), these hypotheses have not really been verified.
Undoubtedly, preadipocytes and adipocytes secrete numerous cytokines and hormones whose receptors are present on different cells of the stromal microenvironment. They are direct and indirect regulators of granulopoiesis and T-lymphocyte commitment, and
modulate macrophage function and secretion. In that respect, independent of nutritional status, BM adipose tissue is involved in the hematopoietic, immune, and inflammation systems. Some arguments indicate that adipogenesis may be the default differentiation pathway of BM mesenchymal progenitors not submitted to paracrine and endocrine agents. This is likely when considering the adipogenesis/osteogenesis balance. Such a counterbalance between adipogenesis and hematopoiesis remains to be demonstrated at the cell level. If transdifferentiation between cells of the mesodermal lineage depending on the current needs of the organism is confirmed, then BM adipose tissue may represent a target for drugs in situations such as aplastic anemia or osteoporosis.
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